It has been thought that there must be covalent binding of low molecular weight drugs, or their metabolites, to larger carrier molecules in order for such drugs and other haptens to stimulate an immune or allergic response. However, since delineation of this mechanism for penicillin allergy was reported over 20 years ago, little progress has been made in identifying reactive metabolites which could initiate allergic responses to other drugs. This project aims to explore the following alternatives: (1) enzyme-inhibitor drugs may stimulate immune responses to drugs when they are firmly bound to their enzymes; (2) host enzymes may covalently link stable drugs with protein carriers, thereby conferring antigenicity; (3) some aspects of drug allergy may be due to drug-induced autoimmune responses, and (4) in vitro binding of drugs or their metabolites to erthrocyte stroma may provide a basis for urgently needed diagnostic tests for drug allergy.